tbuckley/cabot-search huggingface dataset:
Identification of RPTOR mutation as a novel predictor of efficacious immunotherapy in melanoma.
Authors: Yongzhao Li, Qin Zhang, Yuan Tan, Qianqian Duan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

9524 Background: mTOR pathway is known to influence cancer immunity by metabolism reprogramming. RPTOR (Regulatory Associated Protein of MTOR Complex 1), one of mTOR pathway genes, which is involving in control of mammalian target of mTORC1 activity for regulating cell growth and survival. Whether mutations of RPTOR are associated with clinical efficacy of immune checkpoint inhibitors (ICIs) in melanoma is still ambiguous. Methods: In discovery cohort, we retrospective analyzed the genomic data of 418 melanoma samples which derived from seven immunotherapy studies ( http://www.cbioportal.org/ ) to evaluate the relationship between RPTOR mutation status and efficacy of immunotherapy. Then in validation cohort, the predictive value of RPTOR mutation was confirmed in 320 melanomas from MSKCC cohort (http://www.cbioportal.org/). TMB was calculated as the total count of nonsynonymous mutations in coding sequence. We used the CIBERSORT to evaluate the 22 types immune cell infiltration status in TCGA melanoma cohort. Results: The TMB level of RPTOR-mutant patients was higher than RPTOR-wildtype patients in both discovery (Median [IQR]: 43.11[23.76-140.15] vs. 6.13[2.07-13.66], P &lt; 0.001) and validation (Median [IQR]: 37.38[20.17-84.95] vs. 8.85[3.35-21.07], P &lt; 0.001) cohort. In discovery cohort, compared to RPTOR-wildtype patients, the RPTOR-mutant patients achieved prolonged OS (median OS: not reach, NR vs 22.7 months, HR (95%CI): 0.47(0.22-0.99), P = 0.043). This result was confirmed in validation cohort (median OS: NR vs. 42; HR (95%CI): 0.34 (0.11-1.0); P = 0.049). According to analysis of immune cell infiltration status, the mechanism of the predictive values of RPTOR mutations to ICI efficacy may be activated CD4 memory T cell more abundant in RPTOR-mutant tumors. Conclusions: RPTOR mutation is associated with higher TMB in ICI-treated melanoma patients. Survival analysis shows RPTOR mutation have a good link with longer OS after immunotherapy. These findings indicate that RPTOR mutation may serve as a potential predictive biomarker for ICIs in melanoma.
Nivolumab (Nivo) plus ipilimumab (Ipi) 6-month treatment versus continuation in patients with advanced non-small-cell-lung cancer (aNSCLC): 3-year results of the IFCT-1701 DICIPLE phase 3 trial.
Authors: Gerard Zalcman, Anne Madroszyk, Charles Dayen, Olivier Molinier, Thomas Egenod, Didier Debieuvre, Sophie Beaucaire-Danel, Adrien Dixmier, Eric Pichon, Sigolène Galland-Girodet, Etienne Giroux Leprieur, Nicolas Cloarec, Jacques Cadranel, Josiane Otto, Nicolas Poté, Alexandra Langlais, Franck Morin, Martine Antoine, Virginie Westeel, Anne-Claire Toffart
Journal: Journal of Clinical Oncology (2023)

9068 Background: 1 st -line immunotherapy (io) is a standard treatment for patients (pts) with advanced NSCLC devoid of targetable mutation. Classical 2-year io duration does not rely on indubitable evidence. We aimed to assess whether 6-month nivo/ipi was equivalent to continuation until progression or unacceptable toxicity in pts with disease control (DC). Methods: In this multicenter non-inferiority randomized phase 3 trial, eligible treatment-naive pts, age&gt;18, PS 0-1, had stage IV NSCLC and measurable disease. They received Nivo 3 mg/kg q2w plus Ipi 1 mg/kg q6w, until progression or unacceptable toxicity for a maximum of 6-month induction treatment. At 6 months, pts with DC and no severe TRAEs were randomized (1:1) into io continuation (arm A), and observation (arm B). At progression, arm A pts received an investigator's choice 2 nd line platinum-based chemo, while arm B pts resumed double io. Primary endpoint was progression-free survival (PFS). 450 pts x 2 were to be randomized, to achieve 80% power, with 0.025 one-sided a error. Observing that European filing for the io combo was not submitted, the trial's steering committee recommended to stop the accrual on Jan. 2021. Results: From May. 2018 to Jan. 2021, 265 pts (70.6% male, 62.7yr median age, 59% stage IVB, 22.3% SCC, 9.9% PDL1≥50%, 12.2% PDL1&lt;1%) were accrued. 138 (72.6%) pts had disease progression before 6 months, 11 died (5.8%), 30 (15.8%) experienced TRAEs contra-indicating continuation, 11 (5.8%) were deemed ineligible for randomization. 71 pts with DC were randomized. With a median follow-up from randomization of 29.9 months, median PFS was 20.5 (7.4-36.7) months in arm A, 35.2 (21.4-NR) in arm B. 12-month PFS was 55.6% (38.0-69.9) and 81.2% (62.9-91.1), respectively (p=0.08). Adj.HR (arm B vs. arm A) was 0.66, 95%CI (0.28-1.31), p=0.23. OS data, yet immature, did not show any significant difference between both arms (adj.HR arm B vs. A: 0.54 95%CI (0.20-1.49), p=0.23). From randomization, 28.6% G3-5 TRAEs in arm A were observed vs. 2.9% in arm B (p=0.005). Conclusions: The 6-month i.o. interruption for NSCLC patients with DC did not yield significant PFS or OS differences in this prematurely halted trial. Updated OS with a 3-year follow-up, quality of life and biomarker data, will be presented at the meeting. Clinical trial information: NCT03469960 .
The RESECT study: Factors associated with overall survival (OS) and relapse-free survival (RFS) among patients with stages I–III resected NSCLC without known EGFR mutations.
Authors: Jhanelle Elaine Gray, Rachel Salomonsen, Nefeli Georgoulia, Ignacio Diaz Perez, Alice Wang, Ling Cai, Graham Wetherill, Yang Xiao, Claire Fielden, Nasser K. Altorki
Journal: Journal of Clinical Oncology (2023)

8541 Background: Approximately one-third of patients with Stages I–III resected non-small-cell lung cancer (NSCLC) do not survive 5 years from diagnosis. This retrospective observational study analyzed factors associated with OS and real-world (rw) RFS among Stage I–III NSCLC patients before the introduction of immuno-oncology (IO) treatment. Methods: We analyzed data from the US CancerLinQ database for adult patients with no known EGFR mutations and no other cancers, who were diagnosed with Stage I–III NSCLC from 2014–2019 and had surgical resection within 140 days after initial diagnosis. 3081 patients met the study criteria of whom 1677 were Stage I, 853 were Stage II, and 551 were Stage III; 4 Stage I patients who received neoadjuvant or perioperative treatment were excluded (too few for analysis). Most patients received surgery only (71.5%); the rest also received adjuvant (24.7%), neoadjuvant (2.4%) or perioperative (1.5%) treatment, most often chemotherapy ± radiotherapy. Key demographics, clinical characteristics, treatment patterns, and relevant 2-way interactions were considered for inclusion in the model, based on Cox regression analyses and medical insights. Multivariable Cox regression analysis (backwards selection, p&lt;0.05) was used to model OS and rwRFS. Results: In the multivariable analyses (in which no Stage I patients with neoadjuvant or perioperative treatment were included), factors associated with both OS and rwRFS (p&lt;0.05) were disease stage, race, ethnicity, year of diagnosis, ECOG performance status, and neoadjuvant treatment. Factors associated with OS (p&lt;0.05), but not rwRFS, were age, sex, time from diagnosis to surgery, and type of surgery. Factors associated with rwRFS (p&lt;0.05), but not OS, were geographic region, nodal status, and adjuvant treatment in Stage II and III patients but not Stage I patients. Conclusions: This study identified several risk factors associated with OS and rwRFS, many of which are known. Notably, in this analysis, neoadjuvant treatment was associated with both improved OS and rwRFS in Stage II–III patients and was not evaluable in Stage I patients. However, adjuvant treatment was only associated with improved rwRFS, and only in Stage II–III patients. Based on these findings, there remains an unmet need for Stage I–III NSCLC patients. The recent introduction of IO treatment in this setting may help improve patient outcomes.
Real world outcomes of veterans 18-45 years old with acute lymphocytic leukemia.
Authors: Zoe McKinnell, Mustafa Hammudi, Daniel Tuerff, Colleen Hamilton, Martha Antonio, Guoqing Diao, Shanshan Liu, Ramesh Subrahmanyam, Maneesh Rajiv Jain
Journal: Journal of Clinical Oncology (2023)

e18852 Background: Age is a strong prognostic factor in acute lymphocytic leukemia (ALL), with children doing better than adults with the same disease. One hypothesis for this age-based disparity is differences in treatment regimens. Current NCCN guidelines say it is acceptable to treat young adult patients with either pediatric or adult regimens. We conducted a retrospective study of all veterans with ALL diagnosed between the ages of 18-45 since the year 2000 to evaluate the effect of different treatment regimens on overall survival. We also evaluated other disparities that exist among young adults with ALL including race and enrollment in clinical trials. Methods: Electronic medical record data from the Veterans Affairs Corporate Data Warehouse was used to identify patients with an ICD 9 or 10 code for ALL. All patients were chart checked to confirm ALL diagnosis and excluded if they were diagnosed before 2000, had childhood ALL, or if induction protocol was not recorded. 260 patients were included in the final analysis, including 130 treated with a pediatric-inspired regimen. Kaplan-Meier and Cox regression analyses were used to compare overall survival between patients treated on a pediatric-inspired regimen and patients treated on an adult regimen. Multivariate analysis was performed with controls for age, ALL subtype (B, T, mixed phenotype), Ph status, cytogenetic risk (based on modified MRC-ECOG study), obesity (BMI &gt; 30), and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox regression to estimate associations with risk of 5-year death. Results: Patients treated on a pediatric regimen had statistically significant survival gains, with a HR of 0.41, p &lt; 0.001, after controlling for obesity, Ph status, ALL subtype and cytogenetic risk. Pediatric-regimen survival gains were similar for patients ages 30-45 (HR 0.5, p = 0.037). White patients had significantly improved OS compared to people of color (HR 0.55, p = 0.013) after controlling for the aforementioned covariates. Black patients were far less likely (23%) to receive a transplant than non-Black patients (46%). Only 7% of patients were treated on a clinical trial. Patients ages 30-45 were 83% less likely to be enrolled in a clinical trial and 24% less likely to receive a pediatric-regimen than younger adults. Conclusions: This data demonstrates that treatment with a pediatric regimen significantly improves overall survival in patients up to the age of 45. The data also suggests ongoing shortcomings in treatment for young adults with ALL, especially 30 to 45 yos, including persistently high use of adult induction regimens, low rates of referral to clinical trials, and significant racial disparities in bone marrow transplants for Black patients. [Table: see text]
Phase 1 study of SGN-BB228, an investigational CD228 x 4-1BB costimulatory antibody anticalin bispecific, in patients with advanced melanoma and other solid tumors (SGNBB228-001).
Authors: Jason Timothy Henry, Janice M. Mehnert, Erika Rudnicki, Juan Pinelli, Adil Daud
Journal: Journal of Clinical Oncology (2023)

TPS9597 Background: SGN-BB228 is an investigational costimulatory Antibody Anticalin bispecific (Mabcalin) molecule directed to CD228 and 4-1BB. CD228 is a tumor-associated antigen selectively expressed by multiple tumor types including melanoma, mesothelioma, pancreatic, colorectal, and lung cancers with minimal expression in normal tissue. 4-1BB is an inducible costimulatory receptor expressed on activated T cells and other immune cell populations. The clinical development of 4-1BB agonist antibodies has been hampered by limited efficacy and/or poor tolerability at active doses (Segal et al 2017, Segal et al 2018). SGN-BB228 is designed to deliver a potent costimulatory bridge between tumor-specific T cells and tumor cells, potentially localizing antitumor activity to the tumor microenvironment and expanding the therapeutic window for 4-1BB agonism. In vitro, SGN-BB228 shows potent CD228-conditional 4-1BB stimulation and cytotoxic T cell activation (Updegraff et al 2022) providing rationale for evaluating SGN-BB228 in patients (pts) with melanoma or other solid tumors. Methods: SGNBB228-001 (NCT05571839) is a phase 1, open label, multicenter study designed to evaluate the safety, tolerability, PK, and antitumor activity of SGN-BB228 in adults ≥18 years of age with advanced melanoma or other solid tumors. The study includes dose escalation (Part A), dose and schedule optimization (Part B; optional), and dose expansion in disease-specific cohorts (Part C). Parts A and B will enroll pts with histologically or cytologically confirmed metastatic or unresectable cutaneous melanoma, and Part C will enroll pts with cutaneous melanoma, mesothelioma, pancreatic, colorectal, or non-small cell lung cancer. Pts must have disease that is relapsed, refractory, or intolerant to standard of care therapies, ECOG PS 0-1, and adequate organ function. Pts with known active CNS metastases or prior use of agents targeting CD228 or 4-1BB are excluded. Pts with cutaneous melanoma must have received anti PD(L)-1 agent as monotherapy or in combination. Pts with a targetable BRAF mutation must have received, been intolerant to, or declined treatment with BRAF/MEK targeted therapy prior to study entry. Primary endpoints include rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are PK, ORR, DOR, PFS, OS, and incidence of antidrug antibodies. Safety and antitumor activity endpoints will be assessed by dose, schedule, and tumor type using descriptive statistics. The ORR and its 95% CI will be estimated. DOR, PFS, and OS will be estimated using Kaplan-Meier method. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT05571839 .
The incidence and risk factors predictive of bone metastases at initial diagnosis of malignancy.
Authors: Brendan Knapp, Mary Ellen Flanagan, Nikhil Grandhi, Bharath Ganesh, Giordano Fabricio Cittolin Santos, Feng Gao, Pamela P. Samson, Ramaswamy Govindan, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2023)

e18816 Background: Bone metastases are associated with increased morbidity and decreased quality of life in patients with solid tumors. We report here the incidence and predictive factors for bone metastases at initial diagnosis in a large population-based dataset. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients 18 years-old or older and with solid cancers of all stages diagnosed from 2010 to 2019. We calculated the incidence and predictive factors for bone metastases according to demographic and tumor characteristics. Results: Among the 1,132,154 patients identified, 1,075,069 (94.96%) had known bone metastasis status and were eligible for the study. Bone metastases were detected in 55,903 (4.9%) patients. Among patients with bone metastases, the most common primary tumors were lung (44.4%), prostate (19.3%), breast (12.4%), kidney (4.0%), colorectal (2.24%) and pancreas (2.23%). The percentage of bone metastases in patients with non-small cell lung cancer (NSCLC), prostate adenocarcinoma, infiltrating ductal carcinoma of the breast (IDC), and colorectal adenocarcinoma (CRC) was 18.04% (18,123 out of 100,447), 5.92% (9,071 out of 153,325), 2.9% (4,490 out of 154,626), and 1.17% (1,043 out of 89,510) respectively. In addition to T and N stage, independent risk factors by multivariable analysis for bone metastases included female sex and non-squamous histology in NSCLC, black race, hormonal and HER2 status in breast cancer, Gleason score and PSA in prostate cancer, male sex, black race, rectal location, liver metastases and lung metastases in CRC. In univariate analysis, the strongest predictors for bone metastases were N2/3 (28.3%) and T3/4 (24.9%) in NSCLC, T3/4 (15.8%), N2/3 (10.6%), N1 (5.9%) and HER2 positive (4.9%) in IDC, N1 (38.1%), Gleason score 9/10 (22.8%), PSA 98 or higher (19.5%) and PSA 20-97 (16.8%) in prostate cancer, and rectal or rectosigmoid location (1.43% vs 1.05% in colon cancer, p &lt; 0.001) in CRC. Conclusions: Approximately 5% of patients with solid tumors have bone metastases at presentation. In addition to T and N stage, there are several risk factors for bone metastases according to the primary tumor site.
Real world <i>EGFR</i> testing practices for non-small cell lung cancer by thoracic pathology laboratories across Europe.
Authors: Paul Hofman
Journal: Journal of Clinical Oncology (2023)

e21064 Background: Testing for EGFR mutations is an essential recommendation in both the ESMO and ASCO guidelines for metastatic non-squamous NSCLC, and is considered mandatory in European countries. However, in practice, considerable challenges are often faced when performing routine biomarker testing, including access to testing, inadequate tissue samples, and long turnaround times (TATs). Methods: In order to evaluate the real-world EGFR testing practices of thoracic pathology laboratories across Europe, an online survey was set up and validated by The Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories across Europe. The retrospective survey focused on the laboratory organisation and daily practice of pathologists and molecular biologists between 2018 and 2021, and covered the clinical circumstances in which EGFR testing was performed, sample types used, molecular biology techniques performed, average TATs for determining EGFR status, annual EGFR testing rates, laboratory accreditation, and external quality assessment. Results: TATs varied greatly depending on different parameters (notably relating to testing practices and methods used) both between and within countries. TATs were slightly (but non-significantly) faster for liquid biopsy samples (Mean: 7 days, IQR 4.5-12.5) when compared to tissue samples (mean 7 days, IQR 5-15) but were reported to take as long as 20 or 30 days, respectively. Discrepancies in TATs may be due in part to reflex testing practices, as 20% (11/54) of laboratories performed EGFR testing only at the request of the clinician. Many laboratories across Europe still favour targeted sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques, and 45.1% indicated they used targeted sequencing followed by NGS, depending on the case. Reported testing volumes were consistent over time with no significant decrease in the number of EGFR tests performed observed in 2020, despite the increased pressure and difficulties faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42% of molecular biology laboratories for targeted sequencing, and by 42.3% for NGS. 92% (49/53) of laboratories indicated they regularly participate in an EQA scheme. Conclusions: The results of the survey highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there remains large variability in testing capabilities, reflex testing practice and laboratory accreditation, which stresses the urgent need to harmonize budgets and reimbursement in Europe, in addition to harmonization of the technologies and decision-making algorithms.
The impact of COVID-19 on patient involvement in treatment decisions in the US and EU4+UK.
Authors: Elsa Ng, Angelena Moseley, Federico Gallo
Journal: Journal of Clinical Oncology (2023)

e18758 Background: The COVID-19 pandemic has impacted many facets of the healthcare landscape. This study aims to assess the effect of COVID-19 on the evolution of patient involvement in cancer treatment decisions at different time points throughout the pandemic. Methods: The Ipsos COVID-19 Evolution study was run online from April to June 2022 with a total of 353 oncologists responding in the US and EU4+UK (US: 100, EU4+UK: 253). Each physician completed a demographic form and a questionnaire. The demographic form gathered information regarding specialty, practice type and volume of patients treated with anti-cancer drugs in an average month. The questionnaire collected information from physicians on patient workload, diagnosis/tumor characterization, patient management, patient treatment, personal attitude and events, and expectation in the next 6 months. Physicians were required to provide this information by referencing the different time points with regards to the pandemic including pre-pandemic, 1 st peak, Delta/Omicron spread, current state and in the next 6 months. Results: Sampled physicians in the US reported an average of 50% of their managed patients involved in treatment decisions pre-pandemic, while the EU4+UK physicians reported an average of 45% of patients. This increased to 56% and 53% in US and EU4+UK, respectively, at the time of this study and was expected to increase further to 57% and 56%, respectively, in 6 months’ time. While most of the physicians reported an increase in the proportion of patients involved, physicians in the UK reported a drop at the 1 st peak and Delta/Omicron spread compared to pre-pandemic (-1% and -3% respectively). Physicians in Germany reported the highest increase in the volume of patients being involved at the 1 st peak of COVID-19 that quickly dropped during the Delta/Omicron spread (+18% and +6%, respectively). Physicians in Italy reported a much bigger change in the current state and predicted this to grow further in the next 6 months (+27% and +32%, respectively). Besides the recorded growth in the volume of patients involved in treatment decisions, the level of involvement has also increased from pre-pandemic. The average involvement score was 4.8 and 4.7 out of 7 in US and EU4+UK respectively pre-pandemic and grew to 5.2 and 5.0 at the 1 st peak. This further increased to 5.6 and 5.8 at the time of this study. Conclusions: Results from this study highlighted participating physicians reported their patients to be more involved in their cancer treatment decisions compared to pre-pandemic levels and predicted more patients to become increasingly involved in the coming months. Further investigation into the continued impact of the pandemic on patient involvement and the benefits of patient participation would provide further insight into optimal ways to provide better treatment experiences through inclusivity. Further investigation using comparator cohort is warranted.